Arabinofuranosyl-8-azaadenines

ABSTRACT

ARABINOFURANOSYL-8-AZAADENINES ARE PREPARED BT E.G., RING CLOSING APPROPRIATELY BLOCKED 1-AZIDO SUGARS WITH CYANOACETAMIDE TO FORM 1-D-ARABINOFURANOSYL-5-AMINO-4CARBAMOYL-V-TRIAZOLES, WHICH ARE DEHYDRATED TO THE CORRESPONDING NITRILES AND CYCLIZED TO YIELD THE NUCLEOSIDES OF INTEREST, 9-A-D-ARABINOFURANOSYL-8-AZAADENINE, ALONE OR IN THE FORM OF ITS 5&#39;&#39;-PHOSPHATE, IS DEAMINASE RESISTANT AND ACTIVE AGAINST VACCINIA AMD HERPES SIMPLEX VIRUSES. THE CORRESPONDING B ANOMER MAY BE EXPECTED TO SERVE AS A PURINE NUCLEOSIDE ANTAGONIST (AS A SUBSTRATE FOR ONE OR BOTH OF DNA POLYMERASE OR RIBONUCLEOLIDE REDUCTASE AND ITS PRECURSOR 1-B-D-ARABINOFURANOSYL-5-AMINO-4-CARBAMOYL-V-TRIAZOLE TO REGULATE PURINE METABOLISM AND INHIBIT DE NOVO PURINE BIOSYNTHESIS.

States Patent ABSTRACT OF THE DISCLOSURE Arabinofuranosyl-8-azaadenines are prepared by, e.g., ring closing appropriately blocked l-azido sugars with cyanoacetamide to form 1-D-arabinofuranosyl-S-amino-4- carbarnoyl-v-triazoles, which are dehydrated to the corresponding nitriles and cyclized to yield the nucleosides of interest. 9-u-D-AIabinOfuranosyl-8-azaadenine, alone or in the form of its '-phosphate, is deaminase resistant and active against vaccinia and herpes simplex viruses. The corresponding 3 anomer may be expected to serve as a'purine nucleoside antagonist (as a substrate for one or both of DNA polymerase or ribonucleotide reductase) and its precursor l-B-D-arabinofuranosyl-5-amino-4-carbarnoyl-v-triazole to regulate purine metabolism and inhibit de novo purine biosynthesis.

BACKGROUND OF THE INVENTION Derivatives of v-triazolo[4,5-d]pyrimidine such as 8- azaguanine have received considerable attention as purine antagonists in biological systems including viruses and cancer. Growing interest in the biological activity of the nucleosides of like purine analogs has been reflected in studies of 9-,8-D-ribofuranosyl-S-aZaadenine [e.g., Montgomery et al., J. Heterocyclic Chem. 7, 215 1970)], 9-u and B-D-xylofuranosyl-S-azaadenine [Lee et al., Chem. Ind. (London) 2007 (1964)] and 9-}9-D ribofuranosyl- 8-azainosine [e.g., J. A. Montgomery et al., J. Chem. Soc. Chem. Commun., 265 (1970)]. The latter compound has been shown to exhibit significant activity against leukemia L1210 and adenocarcinoma 655. The biological activity of 9-B-D-arabinofuranosyl-adenine (Ara-A) is well documented, and in particular its antiviral action has received considerable study, e.g., as reported by various workers in Antimicrobial Agents Chemotherapy 136, 148, 161, 172, 180 (1968). Although Ara-A is one of but a few synthetic antiviral agents currently under clinical study, its efficacy in that employment is substantially diminished by its susceptibility to enzymatic deamination, whereupon its biological activity is lost.

BRIEF SUMMARY OF THE INVENTION According to this invention there are provided novel arabinofuranosyl-8-azaadenines, as well as novel percursors therefor. A preferred compound of the invention, 9- a-D-arabinofuranosyl-8-azaadenine, exhibits significant activity against herpes simplex and vaccinia viruses while resisting enzymatic deamination. The corresponding [*1 anomer is of interest as a purine nucleoside antagonist. The similarity of its precursor 1-B-D-arabinofuranosyl-5- amino-4-carbamoyl-8-azaadenine to l-fl-D-ribofuranosyl- 5 amino-4-carbamoyl-imidazole (AICAR), a key intermediate in de novo purine biosynthesis, justifies the eX- pectation that the former compound will find utility in the regulation of purine metabolism. Also provided by the invention is a novel method by which the yield of the a-anomer may be maximized.

DETAILED DESCRIPTION OF THE INVENTION The title compounds may be obtained in blocked form by isolation from the isomeric product resulting when 2, 3,S-tri-O-benzyl-D-arabinofuranosyl chloride and the tri 3,826,803 Patented July 30, 1974 methylsilyl derivative of 7-methylthio-v-triazolo [4,5-d] pyrimidine are fused and treated with methanolic ammonia. Preferably, however, the compounds are obtained from novel l-azido arabinosyl sugars, in a manner next discussed with reference to the following flow-sheet, in which glycosyl blocking groups are variously denoted as Ac (acetyl) and B (benzyl). While acetyl is the most commonly used acyl blocking group, it will be understood that any acyl group, e.g., C -C acyl, may be employed to preserve glycosyl hydroxyls against side reactions such as dehydration during synthesis of the compounds of the invention.

BOHzC/ i\ Ac-Acetyl ll B-Benzyl B BOHzC O BOHzC 0 Na k n Km 1, N3 w B B 2 a l A ROHzC O 0 N N R0 l HQN N N HNJ ROHZC 0 I N no Hm-o l ii N R!) 4R=B has ten Rome 0 Rome 0 K l R0 0 I m N N -N HzN V I N u NC 9n=n sszs tit In the first step, the known compound 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride (1) is treated with alkali azide at, e.g., from about 50 to about 150 C. in acetonitrile or other non-aqueous, anion-stabilizing solvent (e.g., DMF, DMSO, hexamethylphosphoric triamide), yielding an anomeric mixture of the corresponding azides (2) and (3). Where the halide reactant (1) is not freshly prepared, about half the azide product is a and half the ,8 anomer, whereas freshly prepared reactant yields subas 14 times more S-amino-1-(2',3',5-tri-0-benzyl-u-D- arabinofuranosyl)-4-carbamoyl v-triazole (4) than corresponding ,8 anomer (7). Cyanoacetamide in water with base is combined with the azide in a non-aqueous solvent such as DMF and the ring closure reaction had at from about C. to about 40 C. (preferably at room temperature). Where a solvent such as tetrahydrofurane is employed, reaction may be at greater temperature, e.-g., at reflux; Compounds (4) and (7) may be separated by silica gel column chromatography, and ring-closed and debenzylated to yield the corresponding novel 9-D- arabinofuranosyl-S-azainosine compounds. In the illustrated case, the carboxamide (4) is dehydrated by treatment with toluene-p-sulphonyl chloride in pyridine to form corresponding cyano compound (9), which is in turn cyclized with diethoxymethyl acetate and methanolic ammonia to afford 2',3',5' tri-O-benzyl-9-a-D-arabinofuranosyl-S-azaadenine (14). The 18 carboxamide (7), of course, may be similarly reacted to afford the blocked 13- arabinosyl-8-azaadenine compound. Removal of benzyl blocking groups from the 8-azaadenine compounds by catalytic hydrogenation affords but low yields, whereas those groups are readily removed from the carbamoyl triazoles (4) and (7). Cyclization of the resulting free nucleosides (6) and (8), however, permits byproduct formation by side reactions with unprotected glycosyl moieties. Accordingly, for example, we protect the glycosyl hydroxyls of (6) with acetyl, affording compound (10) in high yield upon dehydration of the protected compound Cyclization of in methanolic ammonia removes the acyl blocking groups, affording the free nucleoside The ,8 intermediates undergo similar reactions, as appears from the following examples.

EXAMPLE 1 2,3,S-Tri-O-benzyl-D-arabinofuanosyl azides (2) and (3) 2,3,5 Tri-O-benzyl-D-arabinofuranosyl chloride (1) (9.8 g.) was dissolved in acetonitrile (125 ml.) and heated under reflux with sodium azide (10.0 g.) for 2 hr. The mixture was filtered, the residue washed with chloroform and the filtrate and washings combined and evaporated in vacuo to give a tan syrup (8.9 g.). This was chromatographed on a silica gel column eluting with ligroine-ethyl acetate (9:1, v./v.). Two major syrupy components were obtained; one was identified as 2,3,4 tri-O-benzyl-a-D- arabinofuranosyl azide (2) (1.8 g.; 21 111.5 (c 1.0, CHCl IR 2115 cmf (azide); PMR (CD01 5.38 p.p.m. (s, 1, 1 1 Hz., 1-H).

Analysis.Calcd. for C25H27N3O4: C, 70.09; H, 6.11; N, 9.43. Found: C, 70.07; H, 6.00; N, 9.46.

The other major component was 2,3,5-tri-O-benzyI-B- D-arabinofuranosyl azide (3) (5.5 g.; 62%): {M 3 118.2 (c 1.0, CHCl IR 2115 cm? (azide); PMR (CDCl 5.10 p.p.m. (d, 1, 1 =4.0 Hz., 1-H).

Analysis.Calcd for C H N O C, 70.09; H, 6.11; N, 91.43. Found: C, 70.12; H, 6.04; N, 9.30.

EXAMPLE 2 1-(2,3',5'-Tri-O-benzyl-B-D-arabinofuranosyl)-5-amino- 4-carbamoyl-v-triazole (1) and the a-anomer (4) 2,3,5 Tri O-benzyl-fi-D-arabinofuranosyl azide (3) (17.0 g.) was added to a cooled solution of potassium hydroxide (3.2 g.) and cyanoacetamide (4.8 g.) in water (25 ml.) and DMF (250 ml.). The yellow solution was allowed to slowly warm up to room temperature over three hours and then evaporated to dryness in vacuo. The residue was dissolved in methanol (100 ml.) and the solution neutralized with Dowex 50 H+ form 100-200 mesh. After filtration the filtrate was evaporated to dryness in vacuo and the residue partitioned between water and ethyl acetate. The ethyl acetate solution was evaporated to dryness in vacuo and the residual syrup chromatographed on a silica gel column eluting with chloroform-acetone (9:1, v./v.). S-Amino 1 (2,3',5-tri-0-benzyl-u-D-arabinofuranosyl) 4-carbamoyl-v-triazole (4) was obtained as 4, white crystals (14.7 g.; 72%): mp. 6941"; [04 603 (0 1.0, CHCI UV, A351,} 262 nm. (e 11,100); km? 235 nm. (5 9,450); and 259 nm. (e 9,250); A232 237 nm. (e 11,700) and 262 nm. (e 11,400); 1

PMR (CDCl 6.05 p.p.m. (d, 1, I 1.0 Hz., 1'-H).

Analysis.*Calcd for C2gH31N505: C, N, 13.23. FoundzC, 65.70; H, 6.09; N, 12.95.

The minor component obtained from the column was identified as S-amino-l-(2',3',5'-tri-Obenzyl-B-D-arabinofuranosyl) 4 carbamoyl-v-triazole (7) (0.9g; 5%): [M 43.0 (c 1.0, CHCI Uv, m3; 261 nm. (6 10,800); mg 236 nm. (6 9,100) and 259 nm. (6 8,250); A,',,*Z, 237 nm. (6 9,950) and 261 nm. (6 9,100);

PMR (CDCI 6.52 p.p.m. (d, 1, 1 5.0 Hz., 1'-H). Analysis.Calcd for C H N O C, 65.77; H, 5.90; N, 13.23. Found: C, 65.77; H, 5.96; N, 12.98.

Compound (4) was obtained as the sole product on treatment of (2) with cyanoacetamide by the above method.

EXAMPLE 3 5 -Amino- 1- (2',3 ',5 '-tri-O-benzyl-a-D-arabinofuranosyl) 4-cyano-v-triazole (9) UV, N 231 nm. (6 10,800) and 251 (sh) nm. (6 8,300)

max.

'PMR (CDCl 5.20 p.p.m. (s, 2, C-5 NH 6.05 p.p.m.

(d, 1, J ,=3.0 Hz., 1'-H).

Analysis.Calcd for C H N O C, 68.08; H, 5.71; N, 13.69. Found: C, 68.24; H, 5.75; N, 13.71.

EXAMPLE 4 S-Amino-1-(2',3',5'-tri-0-benzyl-8-D-arabinofuranosyl)- 4-cyano-vtriazole (12) The procedure was as for ('9) starting with compound (7). Yield 77%: [M 31.3 (c 1.0, CHC1 IR 2220 cm. (CEN);

UV, A3552 230 nm. (6 10,200) and 250 (sh) nm. (6 6,650);

PMR (CD01 5.25 p.p.m. (s, 2, C-5 NH 6.64 p.p.m. (d, 1, J =6.0 Hz., 1-H).

Analysis.Calcd for C H N O C, 68.08; H, 5.71;

N, 13 Found: C, 68.36; H, 5.86; N, 13.73.

EXAMPLE 5 2',3 ',5 '-Tri-0-benzyl-9-a-D-arabinofuranosyl-8-azaadenine 14) 5 Amino 1 (2,3',5 tri-O-benzoyl-a-D-arabinofuranosyl) 4 cyano-v-triazole (9) (0.5 g.) was heated under reflux in diethoxymethyl acetate (10 ml.) for 4 hr. The yellow solution was evaporated in vacuo and the resulting syrup was dissolved in methanolic ammonia (50 ml., saturated at 0) and allowed to stand in a sealed vessel at room temperature overnight. The solution was evaporated to dryness in vacuo and the residue recrystal- 5, lized from chloroform-,ligroine to give (14). as white needles: mp. 63-65; 1 84.5" (c 1.0, CHCl UV, ME} 261 nm. (a 11,600); 1%? 278 nm. (6 11,300);

" 1 EXAMPLE 6'- 2,3,5'-Tri-0-benzyl-9- 8-D arabinofuranosyl8-azaadenine -The procedure wasasfor compound (14) starting with compound 12) m.p. 165-166; [-a] 48.3 (c 1.0, CHCI S-Amino-l-a-Dwarabinofi ranosyl-4-carbamoyl-v- Method-'1. Sodium waszra'dded,.in small portions, to a stirred suspension of 5 amino 1 --=(2',3',5'-tri-O-benzylwD-arabinofnranosyl)-4-carbamoyl-v-triazole (4) (4.0 g.) in liquid ammonia'-( 100ml.) until the deep blue color persisted. The color was dischargedby careful addition of ammonium chloride and'the-reaction mixture allowed to evaporate to dryness under a stream of nitrogen. The solid residue was trituratedwith -benzene .(50 ml.) and then suspended in 'solventj-E I (ethyl acetatenpropyl alcoholwater: '4: 1 :2, v.7 v./ vupper phase) and the inorganic salts removed'by passage through a-silica gel column eluting withsolvent E. 'Re'crystalliza'tionfrom ethanol gave 1.2 g. (61%) of (6):- m.p. -147-149 -:,=-=[a] 131.7 (0 1.0, H20); a 235 3 ii fl 8. 9 12-6 E M51. 234 nm. (68,550) and 258mm; (6 7,950); A353 234 nm. (e 8,5'50611'61 258 nm. 7,950); x;,{ 234 nm. (e 8,550) and 260 nm. (6 7,700);

M tnM oe' .s 'itp-mgtd; 1.11 2: Hz., 1'-H). 6.52 (s, 2, G5 NH 7.30 (s, 2, C-4 CONH Analysis.Calcd for C l-1 N 0 C, 37.07; H, 5.06; N, 27.02. Found: C, 36.84; H, -5;09"; N; 27.09.

Method 2. A solution of (4) (1.0 g.) in Z-methoxyethanol washydrognated in a lifarr fiydrogenator at 40 p.s.i. and for124 using'f10%. pa]ladium on charcoal (1.0 g.) as catalyst The'rriiXturewas filtered and the filtrate evaporated to dryness in vac'gzoto give 0.47 g. of (6) identical in all respects to the'product from Method liquid ammonia ml.) until the deep blue color persisted. The color was dicharged by careful addition of ammonium chloride and the reaction mixture allowed to evaporate to dryness under a stream of nitrogen. The solid residue was triturated with benzene (20 ml.) and then dissolved in solvent E (ethyl acetate-n-propyl alcohol- Water: 4:1:2, v./v./v.-upper phase) and the inorganic salts removed by passage through a silica gel column eluting with solvent B to give 5-amino-l-a-D-arabinofuranosyl 4 cyano-v-triazole (11) mg.; 32%): mp. 167-168; [01],; 141.3 (c 1.0, H 0); IR 2220 cm.-

UV, A353 228 nm. (6 9,900) and 252 nm. (6 6,750); A331,? 231 nm. (6 8,950) and 252 nm. (e 6,750);

PMR (DMSO-d 5.80 p.p.m. (d, 1, J '=6.0 Hz., 1'-H), 7.32 p.p.m. (S, 2, C-5 NH Analysis.-Calcd for C H N O C, 39.83; H, 4.60; N, 29.04. Found: C, 39.64; H, 4.71; N, 29.31.

EXAMPLE 10 1-(2',3',5'-Tri-0-acetyl-a-D-arabinofuranosyl)-5-arnino- 4-carbamoyl-v-triazole (5 5 Amino 1 oz D arabinofuranosyl-4-carbamoyl- 'v-triazole 6) (250 mg.) was acetylated by standard procedures using acetic anhydride in pyridine to give, after recrystallization from chloroform-ligroine 270 mg. (75%) of (5): mp. 899l; [a] 59.5 (c 1.0, CHCl UV, 13E, 234 nm. (6 9,250) and 261 nm. (6 8,250); LE2 236 nm. (6 9,450) and 258 nm. (6 8,450); M31 236 nm. (e 8,500) and 261 nm. (6 8,100);

PMR (CD01 6.30 p.p.m. (d, 1, 1 :35 Hz., 1'-H), 6.62 p.p.m. (s, 2, C-5 NH 7.30 p.p.m. (s, 2, C-4 CONH Ana'lysis.Calcd for C H N O C, 43.64; H, 4.97; N, 18.18. Found: C, 43.60; H, 4.75; N, 18.10.

EXAMPLE 11 1-(2',3',5'-Tri-0-acetyl-a-D-arabinofuranosyl)-5- amino-4-cyano-v-triazole 10) Method 1. 1 (2,3,5' Tri 0 acetyl-a-D-arabinofuranosyl) 5 amino 4 carbamoyl-v-triazole (5) (500 mg.) was dissolved in dry pyridine (10 ml.) and treated with p-toluenesulphonyl chloride (750 mg.). The solution was left at room temperature overnight and then water added and the solution extracted with ethyl acetate. The organic layer was washed with water and then evapo rated in vacuo to give (10) (340 mg.; 72%) as a syrup:

6 51.7" (c. 1.3, 01101 IR 2220 cm.- (CEN);

UV, 13%,} 228 nm. (5 9,900) and 250 (sh) nm. (6 7,700); N 227 nm. (6 10,500) and 250 (Sh) nm. (6 6,600);

max.

713%,? 232 nm. (a 8,100) and 250 (sh) nm. (6 6,600).

Analysis.-Calcd for C14H17N5O7: C, H, N, 19.07. Found: C, 46.07; H, 4.45; N, 18.90.

Method 2. 5-Amino-1-u-D-arabinofuranosyl-4-cyano- .v-triazole" (11) was acetylated by standard procedures using acetic anhydride in pyridine to give syrupy (10)- identical in all respects to the product from Method '1.

syl)-5-amino-4-cyano-v-triazole (10) (350* mg.) was heated-under reflux indiethoxymethyl acetate (10. ml. for

.4"'hr. The orange solution was evaporated to drynessin va'tlo and the resulting amber syrup was dissolved in methanolic ammonia ('50 ml'., saturated. at '-0) and ial lowed to stand in a sealed vessel at room temperature fortwo days. The solution was evaporated to dryness in vaczgq and the residue recrystallized from'water, to give 0. 13 g. k

EXAMPLE 13 9- 8-D-Arabinofuranosyl-8-azaadenine 17) The procedure was as for compound (15), Method 2, starting with compound (16). Yield 68%; mp. 212-13 C.; 24.0 (c 0.5, H

PMR (DMSO-d 6.50 p.p.rn. (d, 2, J '=6.5 Hz., l'-H), 8.32 p.p.m. (s, 1, H-2).

Analysis.Calcd C H N O H O; C, 38.98; H, 5.09; N, 30.31. Found: C, 39.30; H, 4.83; N, 29.98.

EXAMPLE 14 Compound (11) was tested for antiviral activity by the virus rating (VR) method of Sidwell et al., Proc. Soc. Exp. Biol. Med 131, 1223-30 (1969) V.R. 1.0 is indicative of definite antiviral activity and V.R. of 0.5-0.9 indicative of moderate antiviral activity While V.R. 0.5 suggests slight or no apparent antiviral activity. The following data was taken.

TABLE I.ANTIVIRAL ACTIVITY OF Q-a-D-ARABINOFU- RANOSYL-S-AZAADENINE Virus cone. (CCIDao/ml.) 11

Virus Type 1 Herpes Simplex..-

oomo mom ooooc Do Type 2 Herpes Simplex Do Vaccinia We prepared and tested the isomers S-u-D-arabinofuranosyl-S-azaadenine (in anomeric mixture) and 3-a- D-arabinofuranosyl-tl-azaadenine, finding no comparable antiviral activity.

EXAMPLE As is noted hereinabove, Ara-A suffers from susceptibility to degradation by deaminase, and the compound 9-fi-D-ribofuranosyl-S-azaadenine is also a substrate for the enzyme. Lionel N. Simon et al., Biochem 9, 573 (1970). In our studies, using a large excess (2.3 I.U.) of commercial calf intestine adenosine deaminase, adenosine itself was completely deaminated to inosine in less than two minutes. Under similar conditions (UV spectropho tometer at 279 nm. wavelength), 9-,8-D-arabinofuranosyl-8-azaadenine completely deaminated in a similar period. The corresponding a anomer, however, showed no spectral change and therefore no deamination after 30 minutes. Thin layer chromatography of the reaction mixture against starting materials in the solvent system ethyl acetate/water/n-propanol (422:1), upper phase, confirmed complete deamination of the B anomer and that the a anomer of the invention was unchanged by the enzyme. f

Solubility of the 9-D-arabinofuranosyl-S-azaadenines of the invention may be increased for in viva applications by treating the free nucleoside with excess POCL in tri: methyl phosphate according to the procedure of M. Yoshikawa et al. Bull. Chem. Soc. (Japan) 42, 3505 (1969) to form the 5'-phosphate. Use of acyl rather than benzyl blocked sugar halides as starting materials will, by acyl participation in formation of a stabilized carbonium ion, exclusively form the a-azido sugar where that is desired. Other modifications within the spirit and scope of the invention will occur to the art-skilled in light of this disclosure, by which there have been provided antiviral agents having enhanced resistance to enzymatic deamination, intermediates and methods therefor, and a variety of other compounds of promising utility.

What is claimed is:

1. 9-D-Arabinofuranosyl-8-azaadenine.

2. 9-a-D-Arabinofuranosyl-S-azaadenine.

3. A 5-phosphate of a compound according to claim 1.

4. The 5-phosphate of the compound of claim 2. p

5. An anomeric mixture of 2,3,5-tri-0-benzyl-u-D- arabinofuranosyl azide and 2,3,S-tri-O-benzyl-fl-D-arabinofuranosyl azide.

6. 2,3,5-tri-O-benzyl-a-D-arabinofuranosyl azide.

7. 2,3,S-tri-O-benzyl-B-D-arabinofuranosyl azide;

8. A compound selected from the group consisting of i\ and l N Pal N R0300 b HZNJ RO wherein R is hydrogen, benzyl or C -C acyl, and R is carbamoyl or cyano.

9. Compound (1) of claim 8 wherein R is hydrogen or benzyl and R is cyano.

10. Compound (1) of claim 8 wherein R is hydrogen or benzyl and R is carbamoyl.

11. A compound according to claim 8 wherein R is acetyl.

12. l-a-D-Arabinofuranosyl 5 amino 4-carbamoylv-triazole.

13. 143-D-Arabinofuranosy1 5 v-triazole.

14. A method which comprises the steps of 1) reacting alkali azide and 2,3,S-tri-O-benzyl-D-arabinofuranosyl halide to effect azide displacement of halogen, yielding a first anomeric mixture of 04- and ,B-l-azido sugars, and (2) effecting ring closure by' reacting said sugars with cyanoacetamide, yielding a mixture of 1-(2',3',5'-tri-O- benzyl-a,]3-D-arabinofuranosyl)-5-amino 4 carbamoylv-triazole richer in a-anomer than said first anomeric mixture.

15. A method according to claim 8 wherein sodium azide and 2,3,5-tri-0-benzyl-D-arabinofuranosyl chloride are reacted in Step (1). i

amino-4-carbamoyl- References Cited UNITED STATES PATENTS 3,296,089 1/1967 Nakayama et al. 260--211.5.R 3,407,191 10/1968 Gerzon et a1. 260-2115 R 3,535,207 10/1970 Shiro et a1. 260-2115 R JOHNNIE R. BROWN, Primary Examiner,

U.S. Cl. X.R. 424- 

